The goal of therapy of patients with diabetes mellitus is to prevent acute and chronic complications. Until the causes of diabetic complications are known, presumably therapy should attempt to normalize glucose metabolism as well as glucose concentration. Diabetes is associated with alterations in insulin action, insulin secretion, and counterregulatory hormone concentrations. Furthermore, conventional insulin therapy results in systemic rather than portal insulin delivery. The relative contribution of these abnormalities to carbohydrate intolerance in patients with diabetes mellitus is unknown. Since insulin and glucose concentrations continuously change after food ingestion, the rate of onset of insulin action likely is as important as the ultimate response to a given insulin concentration. Initial experiments will validate and use single and dual isotope methods to test the hypotheses that in the presence of euglycemia, rates of insulin induced suppression of hepatic glucose release and stimulation of glucose uptake are similar in nondiabetic man with both being impaired in diabetic man. Efforts also will be made to assess the contribution of gluconeogenesis to persistent hepatic glucose release during hyperinsulinemia. Next, since under physiologic conditions insulin concentrations virtually never increase unless glucose also increases, and since glucose per se is a powerful regulator of glucose metabolism, computerized infusion systems will be used to produce glucose and insulin profiles that mimic those observed in diabetic and nondiabetic patients following food ingestion. The effects of "nondiabetic" and "diabetic" postprandial glucose profiles will be assessed in diabetic and nondiabetic subjects to quantitate the impact of impaired insulin secretion and insulin action on carbohydrate metabolism and to test the hypotheses that following food ingestion, the effects of glucose per se compensate for hepatic insulin resistance in diabetes. In subsequent experiments the regulatory effects and mechanisms by which physiologic changes in glucagon, growth hormone, and cortisol influence postprandial glucose metabolism will be determined by inhibiting and reproducing the normal postprandial suppression of glucagon and nocturnal increases in growth hormone and cortisol. Finally, the ability of systemic insulin delivery to normalize glucose disposition will be examined by comparing postprandial glucose metabolism and insulin action in patients with combined pancreas/kidney transplants to that observed in nondiabetic kidney transplant patients taking the same immunosuppressive agents as well as to that observed in healthy nondiabetic volunteers. By providing a better understanding of the interactions among changes in insulin action, insulin secretion, route of insulin delivery, and the regulatory effects of glucagon, growth hormone, cortisol and glucose per se on glucose metabolism, the proposed experiments hopefully will lead to more rational and effective forms of therapy for people with diabetes mellitus.